Multiple Sclerosis (MS) is a progressive and disabling disease of the central nervous system (CNS) affecting more than twice as many women as men (1-4). Evidence suggests that neuronal damage begins early in MS (5), with acute axonal injury already present during active demyelination. However, remyelination is known to occur in MS (6,7) where it protects against axon loss (8). Indeed, no significant axonal damage can be observed in remyelinated plaques (5). Axons become less receptive to remyelination as MS progresses. Furthermore, a stroke is a cerebrovascular incident which also leads to neuronal damage. In an experimental model of transient middle cerebral artery occlusion (MCAO) the infarct volume induced by the occlusion was much larger in mice deprived of progesterone receptor (PR knockout mice) than in control intact mice.
The neurodegenerative process of several CNS diseases, including Multiple Sclerosis (MS), Alzheimer's Disease (AD) and Parkinson's Diseases (PD) involve neuroinflamation as well as neurodegeneration, and their frequency increases in women after menopause. Similar neurodegenerative processes are also present in patients suffering from ischemic damage, such as stroke patients, or those who have suffered the effects of a cerebrovascular incident, such as a traumatic brain injury (TBI).
Neuronal damage can also occur in other contexts, such as with a stroke. A stroke is a cerebral vascular incident which results from an interruption in the blood supply to brain cells. Neurons thus can be destroyed because of their sensitivity to oxygen and glucose deprivation, as well as from progressive spreading of nervous tissue damage from an infarct site. There have thus been serious efforts to treat stroke patients to both protect neurons from being destroyed and avoid the spreading of lesions as well as to support regeneration of damaged tissue. Progesterone has previously been identified as an efficient neuroprotective agent. Indeed, progesterone itself is produced at increased rate in brain cells after lesion occurs. Progesterone treatment has also been found to be effective in reducing lesion size following cerebral ischemia in animal models of stroke (18) and has been found to inhibit ischemic brain injury after brain artery occlusion (19). Stroke presents a major public health issue accounting for about over 100,000 cases annually. The only approved treatment for acute stroke is thrombolysis with tissue plasminogen activator (TPA) which has a limited therapeutic window and creates a risk of hemorrhaging.
Progestins such as Nestorone® have been found to exert proliferative and neuroprotective effects in the brain (20,21).
Approximately two-thirds of patients with relapsing-remitting MS are women of reproductive age. (9) It is known that a high level of female sex steroids, such as that which occurs during pregnancy, may be responsible for the remission of symptoms in women with MS. This is especially true during the third trimester when estrogen and progesterone (PROG) levels peak, while the relapse rate increases in the post-partum period. (9)
Women with MS experience changes in their MS symptoms related to pregnancy, the postpartum period, or menopause. In a study conducted in Sweden (10): 40% of the 148 women with MS who were interviewed reported worsening of MS symptoms related to menopause, and more than a fourth of the younger women reported decreased symptoms during pregnancy. Every third woman reported increased symptoms after delivery, suggesting that the sex steroids play a role in the protection (when present in high levels during pregnancy) or worsening of the disease (when they decrease after delivery or at menopause).
An effective treatment strategy for conditions such as MS must also include therapeutic agents that reverse axon demyelination in order to prevent irreversible axon loss. Estrogen and progesterone, female sex hormones, may have beneficial effects on MS and neuroprotection.
In primary hippocampal neuron cultures treated with 17β-E2 and progestins, alone and in combination, 48 hours before glutamate insult, estradiol, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant, but it attenuated the estrogen-induced neuroprotection when coadministered (11). These results may have important implications for the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease by selecting the appropriate molecules for hormone therapy
Progesterone receptor (PR) expression and regulation of neural progenitor cell proliferation was investigated using NPC derived from adult rat brain. Progesterone mediated neural progenitor cell (NPC) proliferation and concomitant regulation of mitotic cell cycle genes is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain (12).